Dataset Information

Antibacterial Spectrum of a Tetrazole-Based Reversible Inhibitor of Serine ?-Lactamases.

ABSTRACT: CTX-M is the most prevalent family of extended-spectrum ?-lactamases. We recently developed a tetrazole-derived noncovalent inhibitor of CTX-M-9. Here, we present the biochemical and microbiological activity of this inhibitor across a representative panel of serine ?-lactamases and Gram-negative bacteria. The compound displayed significant activity against all major subgroups of CTX-M, including CTX-M-15, while it exhibited some low-level inhibition of other serine ?-lactamases. Complex crystal structures with the CTX-M-14 S237A mutant and CTX-M-27 illustrate the binding contribution of specific active-site residues on the ?3 strand. In vitro pharmacokinetic studies revealed drug-like properties and positive prospects for further optimization. These studies suggest that tetrazole-based compounds can provide novel chemotypes for future serine ?-lactamase inhibitor discovery.

SUBMITTER: Pemberton OA

PROVIDER: S-EPMC6105816 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Antibacterial Spectrum of a Tetrazole-Based Reversible Inhibitor of Serine β-Lactamases.

Pemberton Orville A OA Zhang Xiujun X Nichols Derek A DA DeFrees Kyle K Jaishankar Priyadarshini P Bonnet Richard R Adams Jessie J Shaw Lindsey N LN Renslo Adam R AR Chen Yu Y

Antimicrobial agents and chemotherapy 20180727 8

CTX-M is the most prevalent family of extended-spectrum β-lactamases. We recently developed a tetrazole-derived noncovalent inhibitor of CTX-M-9. Here, we present the biochemical and microbiological activity of this inhibitor across a representative panel of serine β-lactamases and Gram-negative bacteria. The compound displayed significant activity against all major subgroups of CTX-M, including CTX-M-15, while it exhibited some low-level inhibition of other serine β-lactamases. Complex crystal ...[more]

PMID: 29844038

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Project description:As shifts in the epidemiology of ?-lactamase-mediated resistance continue, carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are the most urgent threats. Although approved ?-lactam (BL)-?-lactamase inhibitor (BLI) combinations address widespread serine ?-lactamases (SBLs), such as CTX-M-15, none provide broad coverage against either clinically important serine-?-lactamases (KPC, OXA-48) or clinically important metallo-?-lactamases (MBLs; e.g., NDM-1). VNRX-5133 (taniborbactam) is a new cyclic boronate BLI that is in clinical development combined with cefepime for the treatment of infections caused by ?-lactamase-producing CRE and CRPA. Taniborbactam is the first BLI with direct inhibitory activity against Ambler class A, B, C, and D enzymes. From biochemical and structural analyses, taniborbactam exploits substrate mimicry while employing distinct mechanisms to inhibit both SBLs and MBLs. It is a reversible covalent inhibitor of SBLs with slow dissociation and a prolonged active-site residence time (half-life, 30 to 105?min), while in MBLs, it behaves as a competitive inhibitor, with inhibitor constant (Ki ) values ranging from 0.019 to 0.081??M. Inhibition is achieved by mimicking the transition state structure and exploiting interactions with highly conserved active-site residues. In microbiological testing, taniborbactam restored cefepime activity in 33/34 engineered Escherichia coli strains overproducing individual enzymes covering Ambler classes A, B, C, and D, providing up to a 1,024-fold shift in the MIC. Addition of taniborbactam restored the antibacterial activity of cefepime against all 102 Enterobacterales clinical isolates tested and 38/41 P. aeruginosa clinical isolates tested with MIC90s of 1 and 4??g/ml, respectively, representing ?256- and ?32-fold improvements, respectively, in antibacterial activity over that of cefepime alone. The data demonstrate the potent, broad-spectrum rescue of cefepime activity by taniborbactam against clinical isolates of CRE and CRPA.

Dataset Information

Antibacterial Spectrum of a Tetrazole-Based Reversible Inhibitor of Serine ?-Lactamases.

Publications

Antibacterial Spectrum of a Tetrazole-Based Reversible Inhibitor of Serine β-Lactamases.

Similar Datasets

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